Aortic aneurysms are focal dilatations of the arterial wall that are increasingly responsible for significant mortality and morbidity. Although maximum diameter has long been the primary clinical metric for assessing rupture-potential, recent studies demonstrate that wall stress is a far better predictor. This finding is intuitive because aneurysms rupture when wall stress exceeds wall strength. Fortunately, advances in medical imaging and computational biomechanics provide a special opportunity to estimate, on a patient-specific basis, both the hemodynamic loads experienced by an aneurysm and the associated wall stresses that exist within the lesion. Nevertheless, all prior calculations of wall stresses in aortic aneurysms are limited by the assumption of material homogeneity, that is, the assumption that material properties are the same throughout a lesion. It is known, however, that the underlying wall structure is not homogeneous and that the scant data available show regional variations in properties. Indeed, our recent computational simulations of aneurysmal enlargement suggest that composition / properties must vary regionally to enable mechanobiologically driven remodeling. Our recent advances in developing a novel theoretical framework for modeling evolving human aneurysms have revealed two important gaps in the literature that can only be filled using animal models. First, there is a pressing need to measure directly the changing regional mechanical properties of aneurysms as they evolve. Second, there is a need to infer directly from longitudinal data appropriate functional forms for the mass production (e.g., extracellular matrix synthesis and cellular proliferation) and removal (e.g., MMP degradation of matrix and apoptosis), two of the three fundamental classes of constitutive relations needed in models of lesion enlargement and rupture-potential. In this work, we will quantify, for the first time, evolving regional differences in wall composition and cellular phenotype in both dilating (ascending) and dissecting (abdominal) aneurysms from a well accepted angiotensin-II infusion model in ApoE-/- mice over 4 weeks of lesion development; we will also combine in a novel way a 3-D digital image correlation based method and a custom nonlinear sub-domain inverse finite element method to quantify regionally the associated evolving mechanical properties. Finally, we recently showed for the first time that atherosclerotic lesions from ApoE-/- mice differ in stiffness between males and females. Thus, we will delineate, for the first time, potential differences in aortic and aneurysmal wall properties in males and females as well as possible gender-related differences in rates of lesion evolution. This proposal is submitted under the R21 mechanism because we propose to develop a truly novel method for characterizing multiaxial material properties regionally in complex shaped aneurysms, a method that could revolutionize the way vascular experimentation will be done in the future. PUBLIC HEALTH RELEVANCE: Aortic aneurysms are localized dilatations of the aortic wall that are increasingly responsible for death in our aging population. Advances in medical imaging and computer modeling now allow patient-specific calculations that promise to better predict rupture-potential and thereby to better guide clinical intervention. Yet, two main gaps remain in our understanding: how the strength of these aneurysms varies from one region to another and how this strength changes as the aneurysm enlarges. We will develop a new combined optical - computational method that will allow the evolution of these regional differences in strength to be quantified for the very first time. Toward that end, we will use a well accepted mouse model of evolving aneurysms.